The long-term goal of this research project is to improve our ability to prevent, diagnose, and treat human retinal diseases. An improved understanding of the developmental mechanisms employed to construct a normal retina is required to achieve this goal. Our experimental approach uses the fruit fly Drosophila melanogasteras an animal model system to identify and determine the function of conserved genes and pathways that interact during normal retinal development. Recent findings suggest that many developmental parallels exist between Drosophila and mammalian retina. One such parallel is the relationship between R8 photoreceptor specification in Drosophila and ganglion cell determination in mammals. These are the first retinal cells to be specified, express orthologous genes during their development, and play an instructive role in retinal patterning. We have shown that senseless (sens), which encodes a conserved transcription factor, is both necessary and sufficient for R8 photoreceptor differentiation, and is likely to act near the top the genetic pathway controlling R8 specification in Drosophila. Furthermore, the murine homolog of sens, Gill, is expressed in early retinal ganglion cells, suggesting that functional conservation between sens and Gill may also exist. We are therefore investigating the mechanism by which sens controls R8 differentiation in Drosophila. Our preliminary data suggest that sens acts as a regulator of the Epidermal Growth Factor Receptor (EGFR) signaling pathway and may also cooperate with Hedgehog (Hh) signaling during R8 specification. Since these signaling pathways are also involved in mammalian retinal morphogenesis, our proposed studies to characterize sens function and regulation, and to isolate new genes that interact with sens are likely to provide important insights regarding human retinal development. Our Aims are to: 1. Characterize the interaction between sens and the EGFR signaling pathway 2. Elucidate the relationship between sens and the Hh signaling pathway. 3. Dissect sens regulatory elements and identify genes directly controlling sens expression. 4. Identify new genes that interact with sens during eye development. These studies are designed to further elucidate the molecular and genetic mechanisms controlling normal retina development. We use as our developmental system R8 specification in Drosophila, the most powerful genetic model system available. Since the genes and pathways we study are highly conserved in humans, this work will directly impact our understanding of human retinal development.